The activation of
opioid and
neuropeptide FF (
NPFF) receptors plays important roles to modulate nociceptive signal in inflammatory
pain states. Recently, BN-9 (Tyr-D. Ala-Gly-Phe-Gln-Pro-Gln-Arg-Phe-NH2) was pharmacologically characterized as a novel bifunctional agonist at both
opioid and
NPFF receptors. In the present study, the anti-allodynic activity and site(s) of action of BN-9 were assessed in a mouse model of
carrageenan-induced inflammatory
pain. In mice, BN-9 induced a dose-dependent anti-allodinic effect through
opioid receptor at supraspinal or spinal level, and this effect was augmented by pretreatment with the
NPFF receptor antagonist at the same level. In contrast, peripheral administration of BN-9 produced
opioid receptor-mediated anti-
allodynia, which was insensitive of the
NPFF receptor antagonist. In addition, systemic BN-9 produced anti-allodynic effect via
opioid receptors, independent of
NPFF system. Therefore, these data indicate that central, peripheral or systemic administrations of BN-9 exert potent
analgesic activities in inflammatory
pain model via
opioid receptor, and central effects of BN-9 are associated with
NPFF system. Interestingly, systemic anti-
allodynia of BN-9 was blocked by intraperitoneal administration of the
opioid receptor antagonists,
naloxone and
naloxone methiodide, but not by intracerebroventricular injection of the peripherally acting
opioid antagonist naloxone methiodide. Furthermore, BN-9-induced systemic anti-
allodynia was reversed by intraplantar administration of
naloxone, but not by peripheral administration of the
NPFF receptor antagonist. Taken together, our data further suggest that systemic BN-9-induced anti-allodynic effect is mainly mediated by peripheral
opioid receptors, independent of
NPFF receptors.